Project Summary/Abstract Pain is highly prevalent in older adults, but also has a high likelihood of being inadequately treated. Among the reasons for this failure is concern about adverse side effects of currently used analgesics. Older adults, particularly at 85+ years, represent a growing proportion of population, and the declining population of WWII-era veterans is being replaced by veterans surviving more severe injuries than in earlier wars. Thus, there is a strong need to develop new pain treatments with fewer side effects, including those that are particularly problematic for older adults. Opioids acting at the mu (morphine) receptor represent the vast majority of clinically used opioids and remain the most effective at treating moderate to severe pain. However, the use of morphine, and similar compounds, for the management of pain is limited by adverse side effects including respiratory depression, abuse potential, and motor and cognitive impairment. In addition, recent studies have indicated that repeated injection of morphine, for even a few days, can induce glial activation, an inflammatory response that can lead to a paradoxical morphine-induced pain. This may be of particular importance in the treatment of pain in patients already vulnerable to inflammation-induced pathologies, including older adults. The goal of this program is to develop novel mu opioid agonists that provide effective analgesia (antinociception) with fewer adverse side effects relative to morphine. The compounds to be tested are analogs based on the structures of endogenous opioids (endomorphins) discovered in our laboratory that have been shown to produce less respiratory depression and reward (abuse potential) than morphine. Many older adults have compromised respiratory function that can be exacerbated by opioid-induced respiratory depression. Impairment of motor coordination can be particularly serious in patients for whom falls and fractures are more likely to occur and with serious consequences. Opioids are also known to impair cognitive function. Older adults, especially those with mild cognitive impairment, degenerative diseases, or traumatic brain injury, may be especially vulnerable to opioid side-effects. A major hypothesis is that these analogs will produce less neuromotor and cognitive impairment in young, middle-aged, and old rats than morphine. This hypothesis will be tested in a rotorod test of motor coordination, the Morris Water Maze test of spatial memory, and the Object Recognition Task for object memory. Doses of morphine that produce the known impairment on these tasks will be matched by equiantinociceptive doses of the endomorphin analogs to provide a valid comparison of the relative analgesia/side-effect ratio. Effects of acute and chronic treatment will be tested. An additional hypothesis is that glial activation and impairment of neurogenesis will be observed in key brain areas after chronic treatment with morphine but not the analogs. Excessive glial activation and impaired neurogenesis have been associated with cognitive impairment in many studies, and it is anticipated that these neurochemical changes will correlate with the behavior changes measured in this project. If successful, the program will provide novel compounds for more effective pain management with fewer side effects than current medications, with particular value for older adults.